Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 5, pp 1161–1172 | Cite as

Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells

  • Davide Staedler
  • Elita Idrizi
  • Blanka Halamoda Kenzaoui
  • Lucienne Juillerat-Jeanneret
Original Article



Doxorubicin is a first-line chemotherapeutic for breast cancer; however, it is associated with severe side effects to non-tumoral tissues. Thus, it is necessary to develop new therapeutic combinations to improve doxorubicin effects at lower concentration of the drug associated with protective effects for non-tumoral cells. In this work, we evaluated whether the plant-derived flavonoid quercetin may represent such an agent.


The effects of doxorubicin and quercetin as single agents and in combination were evaluated on cell survival, DNA and protein synthesis, oxidative stress, migratory potential and cytoskeleton and nucleus structure in highly invasive and poorly invasive human breast cancer cells in comparison with non-tumoral human breast cells.


In human breast cancer cells, quercetin potentiated antitumor effects of doxorubicin specifically in the highly invasive breast cancer cells and attenuated unwanted cytotoxicity to non-tumoral cells. Quercetin interfered with cell metabolism, GST activity, cytoskeleton and invasive properties specifically in breast tumor cells compared with non-tumoral breast cells. Doxorubicin induced DNA damage in tumor and non-tumor cells; however, quercetin reduced this damage only in non-tumoral cells, thus offering a protective effect for these cells. Quercetin also induced polynucleation in aggressive tumor cells, which was maintained in combination with doxorubicin.


By combining quercetin with doxorubicin, an increase in doxorubicin effects was obtained specifically in the highly invasive breast cancer cells, while in non-tumoral cells quercetin reduced doxorubicin cytotoxic side effects. Thus, quercetin associated with doxorubicin demonstrated very promising properties for developing chemotherapeutics combinations for the therapy of breast cancer.


Quercetin Doxorubicin Breast cancer cells Tyrosine protein kinases Polynucleation Genotoxicity 



We want to thank Dr. C. Brisken for the kind gift of MCF-10A cells, Dr. F. Schmitt for very helpful discussions and comments, Ms. C. Chapuis Bernasconi for excellent technical assistance, and the European Community FP7 project “NanoTest” (grant No 2007-201335) for financial support (to BHK and LJJ). The results shown here are part of Master thesis work of E. Idrizi and D. Staedler at the University of Lausanne (UNIL).

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Hortobagyi GN (1998) Treatment of breast cancer. N Engl J Med 339:974–984PubMedCrossRefGoogle Scholar
  2. 2.
    Andreetta C, Minisini AM, Miscoria M, Puglisi F (2010) First-line chemotherapy with or without biologic agents for metastatic breast cancer. Crit Rev Oncol Hematol 76:99–111PubMedCrossRefGoogle Scholar
  3. 3.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRefGoogle Scholar
  4. 4.
    Gajewski E, Gaur S, Akman SA, Matsumoto L, van Balgooy JN, Doroshow JH (2007) Oxidative DNA base damage in MCF-10A breast epithelial cells at clinically achievable concentrations of doxorubicin. Biochem Pharmacol 73:1947–1956PubMedCrossRefGoogle Scholar
  5. 5.
    Adlercreutz H, Mousavi Y, Hockerstedt K (1992) Diet and breast cancer. Acta Oncol 31:175–181PubMedCrossRefGoogle Scholar
  6. 6.
    Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2:659–668PubMedGoogle Scholar
  7. 7.
    Moon YJ, Wang L, DiCenzo R, Morris ME (2008) Quercetin pharmacokinetics in humans. Biopharm Drug Dispos 29:205–217PubMedCrossRefGoogle Scholar
  8. 8.
    Rodgers EH, Grant MH (1998) The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells. Chem Biol Interact 116:213–228PubMedCrossRefGoogle Scholar
  9. 9.
    Paliwal S, Sundaram J, Mitragotri S (2005) Induction of cancer-specific cytotoxicity towards human prostate and skin cells using quercetin and ultrasound. Br J Cancer 92:499–502PubMedGoogle Scholar
  10. 10.
    Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ (2006) Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem 54:9798–9804PubMedCrossRefGoogle Scholar
  11. 11.
    Bach A, Bender-Sigel J, Schrenk D, Flugel D, Kietzmann K (2010) The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal 13:437–448PubMedCrossRefGoogle Scholar
  12. 12.
    Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S (2009) Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res 29:4629–4632PubMedGoogle Scholar
  13. 13.
    Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FM, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600PubMedCrossRefGoogle Scholar
  14. 14.
    Hsieh TC, Wu JM (2009) Targeting CWR22Rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res 29:4025–4032PubMedGoogle Scholar
  15. 15.
    Ferraresi R, Troiano L, Roat E, Lugli E, Nemes E, Nasi M, Pinti M, Fernandez MI, Cooper EL, Cossarizza A (2005) Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin. Free Radic Res 39:1249–1258PubMedCrossRefGoogle Scholar
  16. 16.
    Lo HW, Ali-Osman F (2007) Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance. Curr.Opin. Pharmacol. 7:367–374PubMedCrossRefGoogle Scholar
  17. 17.
    Tsuchida S, Sato K (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27:337–384PubMedCrossRefGoogle Scholar
  18. 18.
    Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Ann Rev Pharmacol Toxicol 45:51–88CrossRefGoogle Scholar
  19. 19.
    Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D (2000) The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues. Cancer Lett 158:7–16PubMedCrossRefGoogle Scholar
  20. 20.
    Akbas SH, Timur M, Ozben T (2005) The effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB 231 human breast cancer cells. J Surg Res 125(125):49–55PubMedCrossRefGoogle Scholar
  21. 21.
    Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, Dharmawardhane SF (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1:19–27PubMedGoogle Scholar
  22. 22.
    Du G, Lin H, Wang M, Zhang S, Wu X, Lu L, Ji L, Yu L (2010) Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1alpha in tumor and normal cells. Cancer Chemother Pharmacol 65:277–287PubMedCrossRefGoogle Scholar
  23. 23.
    Du G, Lin H, Yang Y, Zhang S, Wu X, Wang M, Ji L, Lu L, Yu L, Han G (2010) Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice. Int Immunopharmacol 10:819–826PubMedCrossRefGoogle Scholar
  24. 24.
    Vaclavikova R, Kondrova E, Ehrlichova M, Boumendjel A, Kovar J, Stopka P, Soucek P, Gut I (2008) The effect of flavonoid derivatives on doxorubicin transport and metabolism. Bioorg Med Chem 16:2034–2042PubMedCrossRefGoogle Scholar
  25. 25.
    Juillerat-Jeanneret L, Chapuis Bernasconi C, Bricod C, Gros S, Trepey S, Benhattar J, Janzer RC (2008) Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine methyl transferase. Cancer Invest 26:597–608PubMedCrossRefGoogle Scholar
  26. 26.
    Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261PubMedCrossRefGoogle Scholar
  27. 27.
    Nagaraja GM, Othman M, Fox BP, Alsaber R, Pellegraino CM, Zeng Y, Khanna R, Tamburini P, Swaroop A, Kandpal RP (2006) Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene 25:2328–2338PubMedCrossRefGoogle Scholar
  28. 28.
    Wang K, Ramji S, Bhathena A, Lee C, Riddick DS (1999) Glutathione S-transferase in wild-type and doxorubicin-resistant MCF-7 human breast cancer cell lines. Xenobiotica 29:155–170PubMedCrossRefGoogle Scholar
  29. 29.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRefGoogle Scholar
  30. 30.
    Topcu Z (2001) DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther 26:405–416PubMedCrossRefGoogle Scholar
  31. 31.
    Momparler RM, Karon M, Siegel SE, Avila F (1976) Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 36:2891–2895PubMedGoogle Scholar
  32. 32.
    Diaz Bessone MI, Berardi DE, Campodonico PB, Todaro LB, Lothstein L, Bal de Kier Joffe ED, Urtreger AJ (2010) Involvement of PKC delta (PKCdelta) in the resistance against different doxorubicin analogs. Breast Cancer Res Treat (in press)Google Scholar
  33. 33.
    Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC (2007) Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93–100PubMedCrossRefGoogle Scholar
  34. 34.
    van Zanden JJ, Ben Hamman O, van Iersel ML, Boeren S, Cnubben NH, Lo Bello M, Vervoort J, van Bladeren PJ, Rietjens IM (2003) Inhibition of human glutathione S-transferase P1–1 by the flavonoid quercetin. Chem Biol Interact 145:139–148PubMedCrossRefGoogle Scholar
  35. 35.
    Gutzeit HO, Henker Y, Kind B, Franz A (2004) Specific interactions of quercetin and other flavonoids with target proteins are revealed by elicited fluorescence. Biochem Biophys Res Commun 318:490–495PubMedCrossRefGoogle Scholar
  36. 36.
    Murakami A, Ashida H, Terao J (2008) Multitargeted cancer prevention by quercetin. Cancer Lett 269:315–325PubMedCrossRefGoogle Scholar
  37. 37.
    Cai Q, Rahn RO, Zhang R (1997) Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett 119:99–107PubMedCrossRefGoogle Scholar
  38. 38.
    Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ (2000) Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2:203–210PubMedCrossRefGoogle Scholar
  39. 39.
    Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z (2008) Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res 68:946–955PubMedCrossRefGoogle Scholar
  40. 40.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedCrossRefGoogle Scholar
  41. 41.
    Singhal RL, Yeh YA, Praja N, Olah E, Sledge GW, Weber G (1995) Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem Biophys Res Commun 208:425–431PubMedCrossRefGoogle Scholar
  42. 42.
    Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, Chen YC (2008) Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 29:1807–1815PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Davide Staedler
    • 1
  • Elita Idrizi
    • 1
  • Blanka Halamoda Kenzaoui
    • 1
  • Lucienne Juillerat-Jeanneret
    • 1
    • 2
  1. 1.Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL)LausanneSwitzerland
  2. 2.Institute of PathologyUniversity of LausanneLausanneSwitzerland

Personalised recommendations